PTT/ PDT-induced microbial apoptosis and wound healing depend on immune activation and macrophage phenotype transformation.

Antibiotics show unsuccessful application in biofilm destruction, which induce chronic infections and emergence of antibiotic resistant bacteria. Photodynamic therapy (PDT) and photothermal therapy (PTT), as widely accepted antimicrobial tools of phototherapy, could effectively activate the immune system and promote the proliferation of wound tissue, thus becoming the most promising therapeutic strategy to replace antibiotics and avoid drug-resistant strains. However, there is no consensus on whether antibacterial and wound healing achieved by PDT/PTT depend not only on the cytotoxic effect of the treatment itself, but also on the activation of host immune system. In this study, CaSiO3-ClO2@PDA-ICG nanoparticles (CCPI NPs) were designed as PDT/PTT antimicrobial model material. With the comparison of healing effect between wide-type mice and severely immunodeficient (C-NKG) mice, the dependence of PDT/PTT-induced microbial apoptosis and wound healing on immune activation and macrophage phenotype transformation was explored and verified. Furthermore, the induced phenotypic transformation of macrophages during PDT/PTT treatment was demonstrated to play crucial role in the improvement of epithelial-mesenchymal transformation (EMT). In summary, this study represents great significance for further identifying the role of immune system activation in antibacterial phototherapy and developing new treatment strategies for biofilm-infected wound healing. STATEMENT OF SIGNIFICANCE: A PDT/PTT combination therapy model nanoparticle was established for biofilm-infected wounds. Both microbial apoptosis and wound healing achieved by PDT/PTT combination therapy were highly dependent on the activated immune system, especially the M2 macrophage phenotype. PDT/PTT could promote the polarization of monocytes to the phenotype of M2 macrophages, which promotes EMT behavior of the tissue at the edge of the wound through the secretion of TGF-ß1, thus accelerating wound healing.

Three-dimension chitosan hydrogel loading melanin composite nanoparticles for wound healing by anti-bacteria, immune activation and macrophage autophagy promotion.

Application of Combined photodynamic therapy (PDT) and photothermal therapy (PTT) has become one of the most promising strategy to replace antibiotics and avoid the epidemic of drug-resistant strains during wound healing. However, high amount of reactive oxygen species (ROS) and high temperature cause severe stress response to normal tissues, leading to potential risks of wound healing. Herein, a three-dimension chitosan hydrogel melanin-glycine-C60 nanoparticles (MGC NPs) were prepared to realized effective anti-bacterial activity, immune activation and macrophage autophagy promotion in three-dimensional wound space without triggering stress response. MGC NP is a composite polymer material composed of natural melanin polymer, oligopeptide and carbon-based material, which showed excellent biological safety. By regulating the peptide length between melanin and C60 and nanoparticle content, a high ROS/heat environment at the upper wound site and a low ROS/heat environment at the lower region adjacent to the wound tissue were established to obtain a three-dimension hydrogel with precise PDT and PTT efficiency in different regions. Highly effective PDT/PTT was used to kill microorganisms in upper region, thus providing a barrier to reduce microbial infection. Mild PDT/PTT in lower region promoted the polarization of M1 macrophage to M2 macrophage and activated autophagy of M2 macrophages, regulating the immune microenvironment and promoting wound repair. In conclusion, the novel three-dimensional PDT/PTT therapy based on natural macromolecules proposed in this study accelerates wound healing through dual pathways on the premise of avoiding wound stress response, which is of great significance for the development of clinical strategies for phototherapy.

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized Clinical Trial.

Importance: Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. Objective: To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. Design, Setting, and Participants: This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Interventions: Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. Main Outcomes and Measures: The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Results: Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Conclusions and Relevance: Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT04063163.

Efficacy and safety of GLS-010 (zimberelimab) in patients with relapsed or refractory classical Hodgkin lymphoma: A multicenter, single-arm, phase II study.

BACKGROUND: GLS-010 (zimberelimab) is a novel, fully human, anti-programmed death-1 monoclonal antibody that shows promising efficacy and safety in advanced solid tumors. This trial aimed to evaluate the efficacy and safety of GLS-010 (zimberelimab) in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r-cHL). METHODS: This phase II, single-arm, open-label, multicenter clinical trial was conducted at 24 centers in China and enrolled patients with r/r-cHL after two or more lines of therapy. The patients were administered intravenous GLS-010 (zimberelimab) (240 mg, once every 2 weeks) until progression, death, unacceptable toxicity, or consent withdrawal. The primary end-point was the objective response rate assessed by an independent radiology review committee (IRC). This study was registered (NCT03655483). RESULTS: Eighty-five patients were enrolled between August 2018 and August 2019. The median follow-up was 15.8 months. Seventy-seven patients (90.6%; 95% confidence interval [CI] 82.3-95.9) had an IRC-assessed objective response. The complete response rate was 32.9% (n = 28). The 12-month progression-free survival and overall survival rates were 78% (95% CI 67.5-85.6) and 99% (95% CI 91.9-99.8), respectively. Treatment-related adverse events (TRAEs) were observed in 92.9% of participants. Grade III or IV TRAEs occurred in 24 (28.2%) of the 85 participants. The most common grade III or IV TRAEs were abnormal hepatic function (5.9%), hyperuricemia (4.7%), decreased neutrophil count (3.5%), and increased weight (3.5%). Only one grade V AE, gastrointestinal infection, occurred. CONCLUSIONS: GLS-010 (zimberelimab) appears to be effective and safe for the treatment of Chinese patients with r/r-cHL. Long-term follow-up is required to confirm these clinical benefits.

pH-Regulating Nanoplatform for the "Double Channel Chase " of Tumor Cells by the Synergistic Cascade between Chlorine Treatment and Methionine-Depletion Starvation Therapy.

During rapid proliferation and metabolism, tumor cells show a high dependence on methionine. The deficiency of methionine exhibits significant inhibition on tumor growth, which provides a potential therapeutic target in tumor therapy. Herein, ClO2-loaded nanoparticles (fluvastatin sodium&metformin&bupivacaine&ClO2@CaSiO3@MnO2-arginine-glycine-aspatic acid (RGD) (MFBC@CMR) NPs) were prepared for synergistic chlorine treatment and methionine-depletion starvation therapy. After outer layer MnO2 was degraded in the high glutathione (GSH) tumor microenvironment (TME), MFBC@CMR NPs released metformin (Me) to target the mitochondria, thus interfering with the tricarboxylic acid (TCA) cycle and promoting the production of lactate. In addition, released fluvastatin sodium (Flu) by the NPs acted on monocarboxylic acid transporter 4 (MCT4) in the cell membrane to inhibit lactate leakage and induce a decrease of intracellular pH, further prompting the NPs to release chlorine dioxide (ClO2), which then oxidized methionine, inhibited tumor growth, and produced large numbers of Cl- in the cytoplasm. Cl- could enter mitochondria through the voltage-dependent anion channel (VDAC) channel, which was opened by bupivacaine (Bup). The disruption of Cl- homeostasis promotes mitochondrial damage and membrane potential decline, leading to the release of cytochrome C (Cyt-C) and apoptosis inducing factor (AIF) and further inducing cell apoptosis. To sum up, the pH-regulating and ClO2-loaded MFBC@CMR nanoplatform can achieve cascade chlorine treatment and methionine-depletion starvation therapy toward tumor cells, which is of great significance for improving the clinical tumor treatment effect.

A multimodal strategy of Fe3O4@ZIF-8/GOx@MnO2 hybrid nanozyme via TME modulation for tumor therapy.

Weak acidity (6.5-6.9) and limited H2O2 level in the tumor microenvironment (TME) usually impact the therapeutic effect of chemodynamic therapy (CDT) for cancer. A Specific TME promotes the formation of an immunosuppressive microenvironment and results in high rate of recurrence and metastasis of cancer. Fe3O4@ZIF-8/GOx@MnO2 multi-layer core shell nanostructure was constructed as a hybrid nanozyme. After magnetic targeting of the tumor site, the outermost MnO2 shell catalyzed H2O2 in TME to produce O2 and was broken due to the reaction with glutathione. Due to the acid response, the ZIF-8 layer would crack and release glucose oxidase (GOx) and Fe3O4. The generated O2 was utilized by GOx in starvation therapy to consume glucose and produce H2O2 and gluconic acid. The Fenton reaction efficiency of Fe(II) was improved by the increased H2O2 concentration and the enhanced acidity in TME. At the same time, the intrinsic photothermal effect of Fe3O4 upon 808 nm laser irradiation promoted the activity of MnO2 and GOx as oxidase, and Fe(II) as catalase-like, and ablated the primary tumor. Moreover, the hybrid nanozyme can facilitate the transformation of M2-type macrophages to M1-type, and strong systemic antitumor immune effect was induced. A synergy of multiple therapeutic modes including starvation therapy, CDT, photothermal therapy (PTT), and immunotherapy can be realized in the hybrid nanozyme for tumor therapy.

A NO/ROS/RNS cascaded-releasing nano-platform for gas/PDT/PTT/immunotherapy of tumors.

Nitric oxide (NO) gas treatment offers a promising strategy for tumor therapy; however, its practical application is still limited due to its poor efficacy and biotoxicity which were caused by gas leakage during blood delivery. Herein, a nano-platform (CMH-OBN) composed of chlorin e6-melanin-hyaluronic acid nanoparticles (Ce6-MNP-HA, CMH) and oxidized bletilla striata polysaccharide microcapsules (Oxi-BSP) carrying NO donors was prepared for responsive and cascaded release of NO, reactive oxygen species (ROS) and its secondary metabolite reactive nitrogen species (RNS) in tumor sites. Melanin not only endowed CMH with good photothermal properties, but also helped Ce6 to produce a large number of ROS under near-infrared (NIR) irradiation. OBN microcapsules, which were sensitive to ROS, can release NO donors under the stimulation of ROS released by CMH nanoparticles under NIR irradiation and can further release NO in the tumor microenvironment (TME) with high expression of glutathione (GSH). NO could further up-regulate soluble guanylate cyclase-cyclic guanosine monophosphate (sGC-cGMP) signal pathways to relieve hypoxia, thus further enhancing the photodynamic therapy (PDT). Moreover, the cascaded release of ROS and NO could produce RNS with higher lethality, which could sequentially initiate the cellular apoptotic procedure and promote immunotherapy by activating T cells at the tumor sites. More interestingly, the CMH-OBN nano-platform could supply magnetic resonance imaging (MRI) and infrared photothermal imaging guidance for tumor therapy. In conclusion, the development of a CMH-OBN nano-platform provides a satisfactory demonstration by combining NO therapy with photothermal therapy (PTT), PDT and immunotherapy for the treatment of cancer.

Image-Guided TME-Improving Nano-Platform for Ca2+ Signal Disturbance and Enhanced Tumor PDT.

Dysfunction of the calcium balancing system and disruption of calcium distribution can induce abnormal intracellular calcium overload, further causing serious damage and even cell death, which provides a potential therapeutic approach for tumor treatment. Herein, a nano-platform, which includes UCNPs-Ce6@RuR@mSiO2 @PL-HA NPs (UCRSPH) and SA-CaO2 nanoparticles, is prepared for improving the tumor micro-environment (TME), Ca2+ signal disturbance as well as enhanced photodynamic tumor therapy (PDT). UCRSPH combined with SA-CaO2 can alter TME and relieve hypoxia of the tumor to realize self-reinforcing PDT under near-IR irradiation (980 nm). The ruthenium red (RuR) in the UCRSPH NPs can be released to the cytoplasm after endocytosis of the nanoparticles, target Ca2+ channel proteins on the endoplasmic reticulum and mitochondria, sarcoplasmic reticulum Ca2+ -ATPase (SERCA), and mitochondrial calcium uniporter (MCU). The combined participation of nanoparticles and RuR promotes Ca2+ imbalance and cytoplasmic calcium overload with the assistance of CaO2 , and provides tumor cells higher sensitivity to PDT. Furthermore, the nano-platform also provides fluorescence imaging and calcification computed tomography imaging for in vivo treatment guidance. In conclusion, this image-guided nano-platform show potential for highly specific, efficient combined therapy against tumor cells with minimal side-effects to normal cells by integrating TME improvement, self-reinforcing PDT, and Ca2+ signal disturbance.

Bevacizumab biosimilar LY01008 compared with bevacizumab (Avastin) as first-line treatment for Chinese patients with unresectable, metastatic, or recurrent non-squamous non-small-cell lung cancer: A multicenter, randomized, double-blinded, phase III trial.

BACKGROUND: Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC). METHODS: Stage IIIB-IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4-6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127). RESULTS: Between December 15th , 2017, and May 15th , 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th , 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1-6) and median duration of treatment of 3.0 (range 0.0-5.1) months. ORR of response-evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80-1.04, within the prespecified equivalence margin of 0.75-1.33). Up to May 15th , 2020, with a median follow-up of 13.6 (range 0.8-28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1-year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups. CONCLUSIONS: LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non-squamous NSCLC patients in the first-line setting.

A Three-in-one ZIFs-Derived CuCo(O)/GOx@PCNs Hybrid Cascade Nanozyme for Immunotherapy/Enhanced Starvation/Photothermal Therapy.

Glucose oxidase (GOx) is regarded as an ideal endogenous natural enzyme for tumor starvation therapy and photothermal therapy (PTT) is a promising strategy for the ablation of primary tumor. In this work, Cu-doped cobalt oxide and porous carbon nanocomposites (CuCo(O)@PCNs) were synthesized from double-layered ZIF-8@ZIF-67 and GOx was loaded in the porous carbon to form a CuCo(O)/GOx@PCNs hybrid nanozyme. CuCo(O) was characterized as the Cu0.3Co2.7O4 phase through X-ray diffraction analysis and it can react with H2O2 to generate O2 and alleviate tumor hypoxia, resulting in the recovered enzymatic activity of GOx and the enhanced starvation therapy. The porous nanocarbon can ablate the primary tumor because of its high photothermal conversion efficiency of 40.04%. The three-in-one functions of oxygen supply, glucose consumption, and photothermal conversion were realized in the ZIFs-derived CuCo(O)/GOx@PCNs nanozyme and the starvation therapy effect was improved by PTT and oxygen supplement. Furthermore, the inhibition effect of CuCo(O)/GOx@PCNs on metastatic tumor is similar to combined therapy of the nanozyme and the immune checkpoint-blocking antibody, α-PD-1. The related antitumor immune mechanism was studied through the analysis of immune-related proinflammatory cytokines and the activated T cells. This work may provide new ideas for the development and application of the ZIFs-derived hybrid nanozyme in tumor therapy and the CuCo(O)/GOx@PCNs nanozyme may be a promising alternative to immune checkpoint inhibitors.

UCPs/Zn2GeO4:Mn2+/g-C3N4 heterojunction engineered injectable thermosensitive hydrogel for oxygen independent breast cancer neoadjuvant photodynamic therapy.

Neoadjuvant chemotherapy for the treatment of breast cancer can provide the option of surgery for patients with a large tumor mass or increase the rate of breast conservation. However, some patients are not sensitive to chemotherapeutic drugs, and therefore this may cause them to miss their optimal chance for surgery. Herein, photodynamic therapy (PDT) was chosen instead of chemotherapy as a neoadjuvant treatment for breast cancer because of its effectiveness against different cancer cells and the lack of side effects in normal tissues. Considering the hypoxic environment of tumors and the tissue penetration depth, a heterojunction Zn2GeO4:Mn2+/g-C3N4 was designed and combined with upconversion materials NaYF4:Yb3+, Tm3+ and hyaluronic acid to form a NaYF4:Yb3+, Tm3+/Zn2GeO4:Mn2+/g-C3N4@HA (UZC@HA) photosensitizer. After intratumoral administration using a thermosensitive hydrogel as a carrier, under a 980 nm laser, UZC@HA can generate holes and electrons to oxidize water to form a hydroxyl radical (˙OH) and react with O2 to produce the superoxide ion (˙O2-), respectively. The thermosensitive hydrogel not only supplies water, but also ensures the high loading capacity of UZC@HA. HA on the UZC can bind specifically with CD44R-overexpressing tumor cells and help the photosensitizer to target tumor sites. Thus, near infrared (NIR) mediated oxygen-independent PDT can be realized. After 12 d of treatment, the tumor mass was significantly reduced and no side effects in normal tissues were observed. Our work shows the potential of the NIR mediated heterojunction UZC@HA to act as a photosensitizer for neoadjuvant PDT in breast cancer and may open a new avenue for exploration of PDT and provide more options for breast cancer patients.

NIR-Driven Water Splitting H2 Production Nanoplatform for H2-Mediated Cascade-Amplifying Synergetic Cancer Therapy.

As a newly emerging treatment strategy for many diseases, hydrogen therapy has attracted a lot of attention because of its excellent biosafety. However, the high diffusivity and low solubility of hydrogen make it difficult to accumulate in local lesions. Herein, we develop a H2 self-generation nanoplatform by in situ water splitting driven by near-infrared (NIR) laser. In this work, core-shell nanoparticles (CSNPs) of NaGdF4:Yb,Tm/g-C3N4/Cu3P (UCC) nanocomposites as core encapsulated with zeolitic imidazolate framework-8 (ZIF-8) modified with folic acid as shell are designed and synthesized. Due to the acid-responsive ZIF-8 shell, enhanced permeability and retention (EPR) effect, and folate receptor-mediated endocytosis, CSNPs are selectively captured by tumor cells. Upon 980 nm laser irradiation, CSNPs exhibit a high production capacity of H2 and active oxygen species (ROS), as well as an appropriate photothermal conversion temperature. Furthermore, rising temperature increases the Fenton reaction rate of Cu(I) with H2O2 and strengthens the curative effect of chemodynamic therapy (CDT). The excess glutathione (GSH) in tumor microenvironment (TME) can deplete positive holes produced in the valence band of g-C3N4 in the g-C3N4/Cu3P Z-scheme heterojunction. GSH also can reduce Cu(II) to Cu(I), ensuring a continuous Fenton reaction. Thus, a NIR-driven H2 production nanoplatform is constructed for H2-mediated cascade-amplifying multimodal synergetic therapy.

Application of a novel thermo-sensitive injectable hydrogel in therapy in situ for drug accurate controlled release.

Local drug injection therapy for tumor site, as a neoadjuvant chemotherapy method, shows important significance in clinical application; however, it obtains unsatisfying therapeutic effect due to the serious toxic and side effect in normal tissues caused by drug diffusion or complexity of the preparation. In this article, the influence factors of the gelling time of traditional Chitosan (CTS) thermo-sensitive hydrogels were analyzed, and the gelling properties were improved significantly, and a thermo-sensitive hydrogel with precisely regulated gelling time was obtained through a green and simple preparation method, and the shortest gelling time (gelling time = 27 ± 2 s) of this hydrogel was 5% of that of the common CTS thermo-sensitive hydrogels. After loaded with different chemotherapy drugs with different pH values (gemctiabin hydrochloride, levofloxacin, and 5-foluorouracil), the hydrogels' gelling performance was not affected, while the gelling time could be shortened by 5-foluorouracil, effectively hindering the drug loss at the early stage of sustained release. in vitro and in vivo experiments proved that precise encapsulation toward tumors with different volumes was achieved by the hydrogels, with minimal damage to surrounding normal tissues and higher utilization of drugs in tumor sites, ultimately achieving better tumor therapeutic effect. In conclusion, the new thermo-sensitive hydrogels with precisely regulated gelling time showed great significance and potential for drug delivery and neoadjuvant chemotherapy.

Overexpression of miR-671-5p indicates a poor prognosis in colon cancer and accelerates proliferation, migration, and invasion of colon cancer cells.

PURPOSE: Colon cancer is one of the common malignancies worldwide, and many genes, including microRNAs (miRNAs), have been demonstrated that associated with progression of various diseases, including cancers. The aim of this study is to investigate the potential role of miR-671-5p in colon cancer. PATIENTS AND METHODS: Reverse transcription-quantitative polymerase chain reaction (qRT-PCR) was performed to detect the expression levels of miR-671-5p in 115 paired colon cancer tissues and adjacent normal tissues, as well as in colon cancer cells. Kaplan-Meier curve and Cox regression analyses were used to estimate the prognostic significance of miR-671-5p in colon cancer. CCK-8 assay, colony-formation assay, Transwell migration and invasion assays were used to evaluate the effects of miR-671-5p on cell proliferation, migration, and invasion in colon cancer. RESULTS: We found that miR-671-5p expression was increased in colon cancer tissues and cell lines. Overexpression of miR-671-5p was found associated with lymph node metastasis, TNM stage, and poor overall survival of patients with colon cancer. By exploiting miR-671-5p mimics and inhibitors, miR-671-5p overexpression significantly increased cell proliferation, migration, and invasion, while downregulation of miR-671-5p inhibited proliferation, migration, and invasion of colon cancer cells. CONCLUSION: Taken together, miR-671-5p may act as an oncogene in colon cancer and promote proliferation, migration, and invasion of colon cancer cells by targeting TRIM67. And it may be a promising prognostic biomarker and therapeutic application for colon cancer treatment.

Biomimetic hydrogel for rapid and scar-free healing of skin wounds inspired by the healing process of oral mucosa.

Inspired by the wound healing characteristics of the oral mucosa, a biomimetic hydrogel was prepared to realize the rapid and scar-free healing of skin wounds. Through monitoring the healing process of injured oral mucosa, we find out that the combination of high, rapid and sequential expression of some growth factors and the sterile-moist microenvironment are crucial for re-epithelialization and precise control of the inflammation process. On the base of our findings, a hydrogel loaded with several functional compounds was prepared to achieve a comprehensive simulation of the oral mucosal trauma microenvironment for skin wound healing. After 7 days treatment, the skin wound area of the treated group was only about 20% of that of the untreated group, and the proportion of collagen type III and type I in the treated group was much higher than that of the untreated group, suggesting lighter scar hyperplasia. The comprehensive treatment strategy of sequential expression of growth factors in combination with maintaining of a sterile and humid environment is expected to have great application prospect in the field of chronic trauma repair and cosmetic surgery. STATEMENT OF SIGNIFICANCE: Long healing time and scar hyperplasia during wound healing have been a serious problem in the past decades of wound healing research. Oral cavity wound healing occurs in an environment that sustains ongoing physical trauma and is rich in bacteria. Despite this, injuries to the mucosal surface often heal faster than cutaneous wounds and leave less noticeable scars. Therefore, in recent years, many scholars have begun to study the healing mechanism of oral mucosa, which supports a new inspiration for the study of skin wound repair: whether the injured skin can achieve a rapid scar-free healing effect similar to oral mucosa? Imitating the biological process of oral mucosa wound healing would be a promising therapeutic strategy in wound healing. Therefore, inspired by the wound healing characteristics of the oral mucosa, a biomimetic gel was prepared to realize the rapid and scar-free healing of skin wounds. Through monitoring the healing process of injured oral mucosa, the combination of high, rapid and sequential expression of some growth factors and sterile-moist microenvironment was crucial for re-epithelialization and precise control of the inflammation process. The comprehensive treatment strategy of sequential expression of growth factors in combination with maintance of a sterile and humid environment implies its potential use in the field of chronic trauma repair and cosmetic surgery.

MicroRNA-191 targets CCAAT/enhanced binding protein ß and functions as an oncogenic molecule in human non-small cell lung carcinoma cells.

The aberrant expression of microRNAs (miRs) may be involved in tumor growth and progression in human non-small cell lung carcinoma (NSCLC). The present study aimed to investigate the potential roles of miR-191 in NSCLC. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to assess protein and/or mRNA levels. Scratch wound healing and transwell assays were performed to determine the NSCLC cell migration and invasion. A luciferase demonstrated that CCAAT/enhanced binding protein ß (C/EBPß) was a target of miR-191. Previously, miR-191 has been reported to act as an oncogenic player in multiple human cancers. C/EBPß has been identified as a target gene of miR-191; however, the roles and underlying mechanisms of miR-191 associated with the regulation of tumor invasion in NSCLC remain unknown. In the present study, it was demonstrated that miR-191 expression levels were higher in human NSCLC tumors compared with in normal adjacent tissue and elevated miR-191 expression levels were closely associated with tumor node metastasis stage in patients with NSCLC. Furthermore, transfection with miR-191 mimic inhibited C/EBPß expression at the mRNA and protein levels and promoted A549 cell migration and invasion. C/EBPß was reported to be the direct target gene of miR-191 using a dual luciferase reporter assay. Finally, C/EBPß siRNA can mimic the effects of miR-191. These findings indicated that miR-191 may function as an oncogene in NSCLC, at least partially due to its negative regulatory on C/EBPß.

The use of heparin, bFGF, and VEGF 145 grafted acellular vascular scaffold in small diameter vascular graft.

We aim to test the application of heparin, bFGF, and VEGF 145 grafted acellular vascular scaffold in small diameter vascular graft. The amount of bFGF and VEGF 145 were determined by ELISA. Femoral artery transplantation was performed. Mechanical strength of acellular vascular scaffolds was determined. Angiography was performed for blood vessel patency. Factor VIII and α2-actin expression was detected by immunohistochemistry. bFGF and VEGF 145 had stable release at 60 and 70 days in vitro, and the release rate of VEGF 145 was slightly slower than that of bFGF. After transplantation, 9 months of the vascular patency rate was 100% at 1, 3, and 9 months, and, was up to 90% at 18 months, while the patency rate in group with grafted heparin only at 1-month was 60%, at 3-month was 40%, at 9-month was 15%, and at 18-month was 10%. The blood vessels taken after 18 months had no significant difference in the mechanical properties between the transplanted and the natural vessels. Positive expression of factor VIII and α2-actin was observed. The heparinized and bFGF and VEGF 145 grafted allogeneic vascular acellular scaffolds are preliminarily obtained, which show good biocompatibility and patency and are of great importance for small diameter vascular graft. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 00B: 000-000, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 672-679, 2019.

Uterine adenomatoid tumor: a clinicopathologic study of 102 cases.

OBJECTIVE: Uterine adenomatoid tumors (UATs) are tubercle without significant clinical features. The study aims to summarize the clinicopathological characteristics of UATs to improve diagnostic accuracy. METHODS: Between January 2014 and December 2015, 4326 uterine specimens were collected from patients who received hysterectomy or myomectomy, of which 102 cases were pathologically confirmed as UATs. The clinical features, pathological parameters and immunohistochemical staining were analyzed. RESULTS: One hundred and two UATs were identified by gross and microscopic examination, which accounts for 2.4% of all the uterine tumors. UATs were usually located in the uterus myometrium, near the serosa or cornua. Most of them were solitary, without an enveloping membrane or clear demarcation. Microscopically, typical features were glandular structures and cavities with various sizes and shapes found within the hyperplastic smooth muscle tissues. Immunohistochemical staining showed that all tumors were positive for HBME-1 and CK (pan). Most of them were positive for CR (89.6%) and D2-40 (92.4%), negative for CD31 and CEA, while cast-off cells in glandular cavities and lymphocytes were positive for LCA. CONCLUSION: Adenomatoid tumors are not very rare in the uterus. The diagnosis of UATs can be improved by carefully gross and microscopic examination. Immnohistachemical staining is helpful for diagnosis and differential diagnosis of UATs.